Circadian Rhythm of Glucocorticoid Administration Entrains Clock Genes in Immune Cells: A DREAM Trial Ancillary Study

Venneri, Mary Anna; Hasenmajer, Valeria; Fiore, Daniela; Sbardella, Emilia; Pofi, Riccardo; Graziadio, Chiara; Gianfrilli, Daniele; Pivonello, Claudia; Negri, Mariarosaria; Naro, Fabio; Grossman, Ashley; Lenzi, Andrea; Pivonello, Rosario; Isidori, Andrea M.

doi:10.1210/jc.2018-00346

Cited by 62 publications

(56 citation statements)

References 36 publications

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“…In order to achieve and mimic the physiological secretion of the deficient hormones it is important to achieve the appropriate dose but also the appropriate timing of hormones replacement. The importance of the timing and profile of hormonal secretion has been recently documented in patients with AI treated with the once-daily MRHC who showed a similar profile in clock gene expression compared with the patients treated by the standard multiple daily-doses GC replacement therapy that exhibited dysregulation in clock gene expression [103] Future studies optimising replacement with maximal patient convenience are to be anticipated.…”

Section: Future Perspectives Of Hypopituitarism Managementsmentioning

confidence: 99%

Management of Hypopituitarism

Alexandraki

Grossman

2019

JCM

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Hypopituitarism includes all clinical conditions that result in partial or complete failure of the anterior and posterior lobe of the pituitary gland’s ability to secrete hormones. The aim of management is usually to replace the target-hormone of hypothalamo-pituitary-endocrine gland axis with the exceptions of secondary hypogonadism when fertility is required, and growth hormone deficiency (GHD), and to safely minimise both symptoms and clinical signs. Adrenocorticotropic hormone deficiency replacement is best performed with the immediate-release oral glucocorticoid hydrocortisone (HC) in 2–3 divided doses. However, novel once-daily modified-release HC targets a more physiological exposure of glucocorticoids. GHD is treated currently with daily subcutaneous GH, but current research is focusing on the development of once-weekly administration of recombinant GH. Hypogonadism is targeted with testosterone replacement in men and on estrogen replacement therapy in women; when fertility is wanted, replacement targets secondary or tertiary levels of hormonal settings. Thyroid-stimulating hormone replacement therapy follows the rules of primary thyroid gland failure with L-thyroxine replacement. Central diabetes insipidus is nowadays replaced by desmopressin. Certain clinical scenarios may have to be promptly managed to avoid short-term or long-term sequelae such as pregnancy in patients with hypopituitarism, pituitary apoplexy, adrenal crisis, and pituitary metastases.

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Section: Future Perspectives Of Hypopituitarism Managementsmentioning

confidence: 99%

Management of Hypopituitarism

Alexandraki

Grossman

2019

JCM

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“…In an attempt to rectify these adverse outcomes, modified and dual release preparations 133,136,137 , as well as continuous 138 and pulsatile pump (The Pulses study, ISRCTN67193733) preparations are being trialled. Initial results are encouraging, with closer mirroring of circadian profiling resulting in alterations in clock gene function 139 and improvements in immune functioning 133 and quality of life 133,136,140,141 . These issues are not only limited to endogenous CORT, but also synthetic glucocorticoids 16 .…”

Section: Potential Mechanisms Underlying This Inhibition Include Disrmentioning

confidence: 99%

The human stress response

2019

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The human stress response has evolved to maintain homeostasis under conditions of real or perceived stress. This objective is achieved through autoregulatory neural and hormonal systems in close association with central and peripheral clocks. The hypothalamic-pituitary-adrenal (HPA) axis is a key regulatory pathway in the maintenance of these homeostatic processes. The end product of this pathway-cortisol-is secreted in a pulsatile pattern, with changes in pulse amplitude creating a circadian pattern. During acute stress, cortisol levels rise and pulsatility is maintained. Although the initial rise in cortisol follows a large surge of adrenocorticotropic hormone (ACTH), if long-term inflammatory stress occurs, ACTH returns to near basal levels while cortisol remains raised as a result of increased adrenal sensitivity. In chronic stress, hypothalamic activation of the pituitary changes from corticotropin-releasing hormone dominant to arginine vasopressin dominant, and cortisol remains raised due at least in part to decreased cortisol metabolism. Acute elevations in cortisol are beneficial to promote survival of the fittest as part of the fight or flight response. However, chronic exposure to stress results in reversal of the beneficial effects with long-term cortisol exposure becoming maladaptive, which can lead to a broad range of problems, including the metabolic syndrome, obesity, cancer, mental health disorders, cardiovascular disease and increased susceptibility to infections. Neuroimmunoendocrine modulation in disease states and glucocorticoidbased therapeutics are also discussed.

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“…Primary or adjuvant medical therapy and radiotherapy may be an option for highly recurrent or particularly aggressive lesions, as well as for lesions at risk of becoming malignant. In the management of these patients, it is essential to minimize the undesirable effects of the treatments, promptly diagnose any hormone deficiencies [19,20] and initiate hormone replacement therapy (HRT), where indicated [21][22][23][24][25]. Central hypogonadism, also known as hypogonadotropic hypogonadism (HH), may occur after surgery, cranial irradiation of parasellar tumours such as craniopharyngioma or germinoma, or hypothalamic-pituitary diseases, such as in patients with glioma.…”

Section: Parasellar Lesions: the Effects Of Treatmentmentioning

confidence: 99%

Late Effects of Parasellar Lesion Treatment: Hypogonadism and Infertility

et al. 2020

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Central hypogonadism, also defined as hypogonadotropic hypogonadism, is a recognized complication of hypothalamic-pituitary-gonadal axis damage following treatment of sellar and parasellar masses. In addition to radiotherapy and surgery, CTLA4-blocking antibodies and alkylating agents such as temozolomide can also lead to hypogonadism, through different mechanisms. Central hypogonadism in boys and girls may lead to pubertal delay or arrest, impairing full development of the genitalia and secondary sexual characteristics. Alternatively, cranial irradiation or ectopic hormone production may instead cause early puberty, affecting hypothalamic control of the gonadostat. Given the reproductive risks, discussion of fertility preservation options and referral to reproductive specialists before treatment is essential. Steroid hormone replacement can interfere with other replacement therapies and may require specific dose adjustments. Adequate gonadotropin stimulation therapy may enable patients to restore gametogenesis and conceive spontaneously. When assisted reproductive technology is needed , protocols must be tailored to account for possible long-term gonadotropin insufficiency prior to stimulation. The aim of this review was to provide an overview of the risk factors for hypogonadism and infertility in patients treated for parasellar lesions and to give a summary of the current recommendations for management and follow-up of these dysfunctions in such patients. We have also briefly summarized evidence on the physiological role of pituitary hormones during pregnancy, focusing on the management of pituitary deficiencies.

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Circadian Rhythm of Glucocorticoid Administration Entrains Clock Genes in Immune Cells: A DREAM Trial Ancillary Study

Abstract: Patients with AI on standard therapy exhibit a dysregulation of circadian genes in PBMCs. The once-daily administration reconditions peripheral tissue gene expression to levels close to controls, paralleling the clinical outcomes of the DREAM trial (NCT02277587).

Cited by 62 publications

References 36 publications

Management of Hypopituitarism

Management of Hypopituitarism

The human stress response

Late Effects of Parasellar Lesion Treatment: Hypogonadism and Infertility

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